MBE Advance Access first published online on June 1, 2007
This version published online on July 25, 2007
Molecular Biology and Evolution, doi:10.1093/molbev/msm110
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Research Article |
Adaptation of HIV-1 to Its Human Host
1 Institute of Genetics, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK
2 Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
3 Laboratoire Retrovirus, Institut de Recherche pour le Developpement and Department of International Health, University of Montpellier I, 34394 Montpellier cedex 9, France
4 Projet Prevention du Sida au Cameroun (PRESICA), Yaounde, Cameroun
Address correspondence to: Paul M. Sharp, Institute of Genetics, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, U.K. Tel: 44-115-823-0335, Fax: 44-115-823-0313, E-mail: plzpms{at}exmail.nottingham.ac.uk
Received for publication April 16, 2007. Revision received May 19, 2007. Accepted for publication May 22, 2007.
Human immunodeficiency virus type 1 (HIV-1) originated from three independent cross-species transmissions of simian immunodeficiency virus (SIVcpzPtt) infecting chimpanzees (Pan troglodytes troglodytes) in west central Africa, giving rise to pandemic (group M) and non-pandemic (groups N and O) clades of HIV-1. To identify host-specific adaptations in HIV-1 we compared the inferred ancestral sequences of HIV-1 groups M, N and O to 10 full length genome sequences of SIVcpzPtt and four of the outlying but closely related SIVcpzPts (from P. t. schweinfurthii). This analysis revealed a single site that was completely conserved among SIVcpzPtt strains but different (due to the same change) in all three groups of HIV-1. This site, Gag-30, lies within p17, the gag-encoded matrix protein. It is Met in SIVcpzPtt, underwent a conservative replacement by Leu in one lineage of SIVcpzPts but changed radically to Arg on all three lineages leading to HIV-1. During subsequent diversification this site has been conserved as a basic residue (Arg or Lys) in most lineages of HIV-1. Retrospective analysis revealed that Gag-30 had reverted to Met in a previous experiment in which HIV-1 was passaged through chimpanzees. To examine whether this substitution conferred a species specific growth advantage, we used site-directed mutagenesis to generate variants of these chimpanzee-adapted HIV-1 strains with Lys at Gag-30, and tested their replication in both human and chimpanzee CD4+ T lymphocytes. Remarkably, viruses encoding Met replicated to higher titers than viruses encoding Lys in chimpanzee T cells, but the opposite was found in human T cells. Taken together, these observations provide compelling evidence for host-specific adaptation during the emergence of HIV-1 and identify the viral matrix protein as a modulator of viral fitness following transmission to the new human host.
Key Words: HIV-1 • SIV • matrix protein • cross-species transmission • host-specific adaptation
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